P370: EFFICACY AND SAFETY OF THE THIRD-GENERATION TKI OLVEREMBATINIB IN ADULTS PH/BCR-ABL1-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA WITH T315I MUTATION AND RELAPSED/REFRACTORY DISEASE
Authors: Weiyang Liu, Yuanfang Liu, Yongmei Zhu, Xiangqin Weng, Cheng Wang, Wanyan Ouyang, Jie Xu, Jin Wang, Jian‑qing MI
Journal: HemaSphere (2023)

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved the outcomes of patients (pts) with Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph/BCR-ABL1+ ALL). Mutation of the ABL1 kinase domain, especially T315I, is the main mechanism of resistance to the first and second-generation TKIs. Olverembatinib is a novel third-generation TKI developed in China and approved in Dec. 2021, which has shown remarkable efficacy and safety in CML, but few reports are available in Ph/BCR-ABL1+ ALL. Aims: Herein, we report the updated results of olverembatinib in Ph/BCR-ABL1+ ALL pts with T315I mutation or relapsed/refractory (R/R) disease in our institution. Methods: In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone). Efficacy was assessed by CR rate, MRD negative (MRD-, <10-4) rate by multiparameter flow cytometry (MFC), CMR (BCR-ABL1 transcript<10-5) rate by RT-qPCR, as well as the survival data. PFS and OS were both calculated from the start of olverembatinib. Adverse events (AEs) were assessed and graded according to CTCAE v5.0. Results: From Dec. 2021 to Dec. 2022, 21 pts with Ph/BCR-ABL1+ ALL were treated with olverembatinib due to T315I mutation or R/R disease, with a median age of 60 years (range,23-76). Among 21 pts, 11 were in CR1, with molecular R/R disease detected by MFC or RT-qPCR. The other 10 had hematological R/R diseases, including 1 with refractory central nervous system leukemia. Median time from diagnosis to the administration of olverembatinib was 6 months (range, 2-41). T315I mutation was detected in 16 pts, including 6 with additional mutations. Among 11 pts with molecular R/R diseases, MRD- and CMR rates were 72.7% and 63.6%, with a median time of 1 month (range, 1-4) to achieve MRD-. Among 10 pts with hematological R/R disease, the CR, MRD- and CMR rates were 70%, 50% and 40%, respectively, with a median time of 2 months (range, 1-4) to achieve CR. ORR, MRD- and CMR rates for the entire cohort were 71.4%, 61.9% and 52.4%. In pts with T315I mutation, MRD- and CMR rates were 75% and 62%, and were both 20% in those without T315I mutation, suggesting that pts with T315I could achieve better molecular response (Figure 1A). Further comparison between pts with T315I single mutation and combined mutations showed that the former could respond better to olverembatinib (Figure 1B). By Jan. 15, 2023, the median follow-up time was 6 months (range, 1-10), and PFS and OS rates were 51.5% and 64.5%. Among 21 pts, 11 remained MRD- or CMR, 4 had no response or disease recurrence again, while 6 died due to disease progression. MRD- or CMR responders had significantly better PFS and OS (Figure 1C, 1D). All the 6 pts bridging allo-HSCT after Olverembatinib-based therapy achieved sustained CMR with a survival superiority (Figure 1E, 1F). As for safety analysis, all pts experienced at least 1 treatment-related AE. Most of the non-hematological AEs were G1-2, and most of the G3-4 AEs were hematological, possibly related to chemotherapy. The incidence of G3-4 cardiovascular AEs (CVEs) was 9.5% (2 pts), only 1 pt needed dose adjustment due to G4 CVE (hemorrhagic Infarct of the intestine). No death related to olverembatinib was observed.Summary/Conclusion: The novel third-generation TKI Olverembatinib is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with molecular or hematological R/R disease, especially in pts with T315I mutation. In addition, bridging allo-HSCT after MRD clearance could be a better choice to improve PFS and OS. These results laid an essential foundation for subsequent prospective clinical trials. Keywords: BCR::ABL, Tyrosine kinase inhibitor, Acute lymphoblastic leukemia